Physiologically-based pharmacokinetic model to predict doxorubicin and paclitaxel exposure in infants through breast milk

Abstract

Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%-1.7% and 0.1%-1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.

FIGURE 1

IV and oral (PO) paclitaxel administration in the base model and the model with the worst‐case scenario parameters with corresponding bioavailability and a comparison in the peripheral venous blood exposure of the base model and worst‐case parameter model after oral administration. Bioavailability and differences in exposure were calculated using the AUC_0‐inf. The black vertical lines represent the time of the last administered dose. AUC_0‐inf, area under the plasma‐concentration time curve extrapolated until infinity.

FIGURE 2

IV and oral (PO) doxorubicin administration in the base model and the model with the worst‐case scenario parameters with corresponding bioavailability and a comparison in the peripheral venous blood exposure of the base model and worst‐case parameter model after oral administration. Bioavailability and differences in exposure were calculated using the AUC_0‐inf, bioavailability calculated with AUC_0‐4000h were much lower at 4% and 20% for the base model and worst‐case parameter model, respectively. The black vertical lines represent the time of the last administered dose. AUC_0‐inf, area under the plasma‐concentration time curve extrapolated until infinity.

FIGURE 3

Simulation results with worst‐case scenario predictions of paclitaxel exposure in a population of 500 infants between 0 to 1 years old. Concentration‐time curves (a), AUC_0‐inf (b) and C _max (c) for peripheral venous blood, and small and large intestines for the situations in which 0, 1, 2, or 3 days of breast milk are discarded after maternal administration with 90% prediction intervals. The horizontal dashed line represents the lowest in vitro cell death half‐maximal inhibitory concentration for paclitaxel found in literature (2.5 nM, after a 24 h exposure). AUC_0‐inf, area under the plasma‐concentration time curve extrapolated till infinity; C _max, peak concentrations.

FIGURE 4

Days of breast milk that have to be discarded after maternal chemotherapy administration (new cycle) to prevent worst‐case scenario predicted paclitaxel and doxorubicin concentrations of the upper 95th quantile of the predicted C _max values in the breastfed infant population to reach greater than 10, between five and 10, between one and five and less than onefold levels of in vitro cell death IC₅₀ in plasma, heart (doxorubicin only) or intestines. In vitro cell death IC₅₀ used are 2.5 and 270 nM for paclitaxel and doxorubicin, respectively. Concentrations in the 4th cycle were used for doxorubicin because of accumulation over cycles. We chose to use a 7 and 14 day cycle for paclitaxel and doxorubicin, respectively, because these are the most frequently used schedules. AUC_0‐inf, area under the plasma‐concentration time curve extrapolated till infinity; C _max, peak concentrations; IC₅₀, half‐maximal inhibitory concentration.

FIGURE 5

Simulation results with worst‐case scenario predictions of doxorubicin exposure in a population of 500 infants between 0 and 1 years old. Concentration‐time curves (a), AUC_0‐inf (b) and C _max (c) for peripheral venous blood, heart, small and large intestines for the situations in which 0, 1, 2 or 3 days of breast milk are discarded after maternal administration with 90% prediction intervals. The horizontal dashed line represents the lowest in vitro cell death IC₅₀ for doxorubicin found in literature (270 nM, after a 72 h exposure). AUC_0‐inf, area under the plasma‐concentration time curve extrapolated till infinity; C _max, peak concentrations; IC₅₀, half‐maximal inhibitory concentration.

FIGURE 6

Clinical plasma concentrations of doxorubicin in on‐treatment children between 11 and 56 weeks old (dots) after administration of a doxorubicin infusion with a duration between 0.07 and 4.5 h. Lines are simulations in infant of 0.25, 0.5 and 1 years old with the worst‐case parameter model after a doxorubicin infusion of 0.7 (red), 1 (green), and 1.4 mg/kg with a duration of 0.5 h. Note that infusion duration is shorter for some of the simulations than for some of the clinical plasma concentrations and that the worst‐case parameters in the model are absorption related and therefore have minimal effect on exposure after i.v. administration.